Atherosclerosis最新文献

{"title":"Cell surface nucleolin promotes endothelial cell pyroptosis in atherosclerosis through RASSF2","authors":"Li Fang,&nbsp;Zhijie Shen,&nbsp;Dan Huang,&nbsp;Chenyu Lou,&nbsp;Yalan Yu,&nbsp;Yuli Lin,&nbsp;Yinzhuang Zhang","doi":"10.1016/j.atherosclerosis.2026.120715","DOIUrl":"10.1016/j.atherosclerosis.2026.120715","url":null,"abstract":"<div><h3>Background and aims</h3><div>Increasing evidence indicates that modulating pyroptosis in endothelial cells (ECs) can alleviate atherosclerosis (AS) progression; however, despite reports that nucleolin (NCL) regulates vascular smooth muscle cell proliferation in AS, the potential mechanism by which cell surface NCL mediates pyroptosis in ECs during AS remains poorly understood.</div></div><div><h3>Methods</h3><div>AS was induced in ApoE^−/− mice by feeding a high-fat diet, after which aortic lesions were evaluated. Pyroptosis, inflammatory status, and NCL expression in ECs of the aortic root were then assessed. The effects of NLRP3 inflammasome inhibition and NCL modulation on atherosclerotic lesion severity in AS mice, as well as on pyroptosis in ox-LDL-stimulated ECs, were systematically investigated. In addition, the mechanistic role of NCL in AS was further explored using approaches including immunoprecipitation-mass spectrometry (IP-MS).</div></div><div><h3>Results</h3><div>AS model mice developed severe aortic lesions accompanied by pronounced EC pyroptosis and inflammation, together with elevated NCL expression in ECs of the aortic root. Both inhibition of NLRP3 and NCL knockdown alleviated atherosclerotic lesion severity in ApoE^−/− mice and attenuated ox-LDL-induced EC pyroptosis. Mechanistically, cell-surface NCL interacted with RASSF2 via its RNA-binding domain, and suppression of NCL decreased nuclear RASSF2 expression. NCL facilitated the translocation of RASSF2 into the nucleus, thereby exacerbating EC pyroptosis and amplifying inflammatory responses.</div></div><div><h3>Conclusions</h3><div>This study demonstrates that, in AS, NCL exacerbates EC pyroptosis and promotes disease progression by facilitating nuclear transport of RASSF2. This study defines the mechanistic roles of NCL in AS, thereby identifying a new molecular pathway and suggesting potential therapeutic targets.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"415 ","pages":"Article 120715"},"PeriodicalIF":5.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147525671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to immunopeptidomics analysis of human atherosclerosis plaques identifies antigenic drivers of atherosclerosis[Atherosclerosis, (409), October 2025, 120509]","authors":"F. Lozano Vigario ,&nbsp;J. Molenaar ,&nbsp;I. Simó Vesperinas ,&nbsp;M. van der Zon ,&nbsp;N.S.A. Crone ,&nbsp;M.J.M. deJong ,&nbsp;E. Hemme ,&nbsp;M.A.C. Depuydt ,&nbsp;L. Delfos ,&nbsp;J. de Mol ,&nbsp;M.N. Bernabé Kleijn ,&nbsp;J.A.H.M. Peeters ,&nbsp;A. Wezel ,&nbsp;H.J. Smeets ,&nbsp;R.T.N. Tjokrodirijo ,&nbsp;A.H. deRu ,&nbsp;A. Kros ,&nbsp;P.H.A. Quax ,&nbsp;M.R. de Vries ,&nbsp;J. Kuiper ,&nbsp;B. Slütter","doi":"10.1016/j.atherosclerosis.2025.120520","DOIUrl":"10.1016/j.atherosclerosis.2025.120520","url":null,"abstract":"","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"415 ","pages":"Article 120520"},"PeriodicalIF":5.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147301284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply: Plaque regression: Risk status or ApoB exposure?","authors":"Yasushi Ueki ,&nbsp;Sylvain Losdat ,&nbsp;Konstantinos C. Koskinas ,&nbsp;Lorenz Räber","doi":"10.1016/j.atherosclerosis.2026.120720","DOIUrl":"10.1016/j.atherosclerosis.2026.120720","url":null,"abstract":"","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"415 ","pages":"Article 120720"},"PeriodicalIF":5.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147740201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNMT3A clonal hematopoiesis is associated with cardiovascular disease in women","authors":"Benedek Halmos ,&nbsp;Jonas B. Salzbrunn ,&nbsp;Isabelle A. van Zeventer ,&nbsp;Aniek O. de Graaf ,&nbsp;Silke E. Miedema ,&nbsp;Judith M. Vonk ,&nbsp;M. Yldau van der Ende ,&nbsp;Pim van der Harst ,&nbsp;Rozemarijn Vliegenthart ,&nbsp;Joop H. Jansen ,&nbsp;Gerwin Huls ,&nbsp;Marit Westerterp","doi":"10.1016/j.atherosclerosis.2026.120722","DOIUrl":"10.1016/j.atherosclerosis.2026.120722","url":null,"abstract":"<div><h3>Background</h3><div>Clonal hematopoiesis (CH) is an independent risk factor for cardiovascular disease (CVD). Targeted next generation sequencing (NGS) studies have highlighted the contribution of smaller clones to CVD, particularly for <em>DNMT3A</em> and <em>TET2</em> CH, the most frequent CH mutations. <em>DNMT3A</em> CH occurs more frequently in women than men. Whether sex affects the association between CH and CVD is unknown.</div></div><div><h3>Methods</h3><div>We included 5508 participants from the Lifelines cohort, who had previously undergone targeted NGS. Our cohort is enriched for blood count abnormalities. We investigated the sex-specific associations between CH and prior myocardial infarction (MI) or coronary artery calcium (CAC) and evaluated the association of sex or prior MI with clonal expansion.</div></div><div><h3>Results</h3><div>We identified 2103 participants carrying CH. <em>DNMT3A</em> CH occurred more frequently in women than men (OR 1.29; <em>p</em> = 5.2 × 10⁻⁴). Women with <em>DNMT3A</em> CH had a higher odds of prior MI (OR 1.77; <em>p</em> = 2.1 × 10⁻²), while men did not (OR 0.98; <em>p</em> = 8.8 × 10⁻¹; <em>P</em>_interaction = 4.4 × 10⁻²). Sex or prior MI did not affect clonal expansion. <em>DNMT3A</em> clone size positively associated with age- and sex-adjusted CAC percentile scores in women (B 28.97; <em>p</em> = 9.7 × 10⁻³), but not in men (B 2.34; <em>p</em> = 8.3 × 10⁻¹; <em>P</em>_interaction = 8.9 × 10⁻²). Women with a higher-than-average <em>DNMT3A</em> clonal expansion had higher CAC percentile scores compared to women with lower-than-average clonal expansion, independent of initial <em>DNMT3A</em> clone size (B 16.76; <em>p</em> = 1.1 × 10⁻²).</div></div><div><h3>Conclusions</h3><div><em>DNMT3A</em> CH is associated with previous MI and higher atherosclerotic burden only in women, highlighting the need to better understand the sex-specific risks that CH may confer on CVD.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"415 ","pages":"Article 120722"},"PeriodicalIF":5.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147600190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deficiency of transcription factor E4BP4 suppresses neointimal formation after vascular injury","authors":"Fumie Ohtomo ,&nbsp;Kikuo Isoda ,&nbsp;Tomiharu Niida ,&nbsp;Tomoyasu Kadoguchi ,&nbsp;Masahiro Kuwabara ,&nbsp;Tohru Minamino","doi":"10.1016/j.atherosclerosis.2026.120677","DOIUrl":"10.1016/j.atherosclerosis.2026.120677","url":null,"abstract":"<div><h3>Background and aims</h3><div>Adventitial inflammation is involved in the onset of Takayasu arteritis (TAK) and the formation of pathological conditions. E4BP4 is a transcription factor involved in regulating circadian rhythms and cell viability, and it has been reported that E4BP4 regulates inflammation. Therefore, we decided to investigate the role of E4BP4 in neointimal formation after adventitial inflammation induced by cuff injury.</div></div><div><h3>Methods</h3><div>Using E4BP4-deficient (E4BP4−/−) and wild-type (WT) mice, we investigated neointimal formation 2 weeks after femoral artery injury induced by an external vascular cuff model. Intimal and medial area were measured, and the intima/media ratio was calculated.</div></div><div><h3>Results</h3><div>The mean intimal area and the intima/media ratio of E4BP4−/− mice decreased by 86 % and 97%, respectively, compared with WT mice. Immunohistochemistry for NK cell (NKp46) revealed the percentage of NKp46 positive area in the adventitia of E4BP4−/− mice was significantly lower compared with WT mice at 14 days post-injury. Furthermore, the positive area of CD8α (cytotoxic T lymphocyte (CTL)), IL-6, TNF-α and IFN-γ in the intima of E4BP4−/− mice was much smaller than those of WT mice.</div></div><div><h3>Conclusions</h3><div>Deficiency of E4BP4 reduced the inflammatory cytokines and suppressed neointimal formation after adventitial inflammation. We also observed a decrease in both NKp46 and CD8α, suggesting that proliferation of NK cell and CTL is impaired by E4BP4 deficiency. The present study is the first to demonstrate that E4BP4 plays an important role in the increase of neointimal formation after inflammation in vivo, thus suggesting that E4BP4 inhibition may represent a useful strategy to inhibit vascular inflammation, such as TAK.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"415 ","pages":"Article 120677"},"PeriodicalIF":5.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146187550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ischemic stroke and intracranial large-artery disease risk in familial hypercholesterolemia: A prospective Japanese study","authors":"Yorito Hattori ,&nbsp;Kotaro Noda ,&nbsp;Mika Hori ,&nbsp;Yuriko Nakaoku ,&nbsp;Soshiro Ogata ,&nbsp;Hiroaki Murata ,&nbsp;Kunihiro Nishimura ,&nbsp;Atsushi Nagai ,&nbsp;Shuhei Yamaguchi ,&nbsp;Mariko Harada-Shiba ,&nbsp;Masafumi Ihara","doi":"10.1016/j.atherosclerosis.2026.120674","DOIUrl":"10.1016/j.atherosclerosis.2026.120674","url":null,"abstract":"<div><h3>Background and aims</h3><div>The contribution of dyslipidemia to stroke risk is generally considered weaker than that of hypertension and diabetes. However, some previous studies suggest that dyslipidemia is associated with intracranial major artery stenosis (ICAS) and ischemic stroke, particularly in Asians populations, who are more susceptible to ICAS than Caucasians. We hypothesized that dyslipidemia, and specifically familial hypercholesterolemia (FH), may play a different role in the development of stroke in Asian populations. This study aimed to assess the prevalence and incidence of symptomatic ischemic stroke and ICAS in Japanese patients with FH compared to individuals undergoing Brain Dock.</div></div><div><h3>Methods</h3><div>This prospective longitudinal study included FH patients who visited a lipid clinic and underwent brain magnetic resonance imaging (MRI) at the National Cerebral and Cardiovascular Center, alongside participants who underwent brain MRI as part of the Brain Dock screening program in Japan.</div></div><div><h3>Results</h3><div>In total, 3178 participants who underwent Brain Dock and 150 patients with FH were included. FH was an independent risk factor of a higher prevalence of ICAS (≥50%; adjusted odds ratio: 17.82, 95% confidence interval [CI]: 8.74–36.36), and high symptomatic ischemic stroke incidence (adjusted hazard ratio [aHR]: 5.83, 95% CI: 2.03–16.77). The presence of ICAS was significantly associated with symptomatic ischemic stroke in patients with FH (aHR: 7.73, 95% CI: 1.53–39.06).</div></div><div><h3>Conclusions</h3><div>FH may confer a high risk for symptomatic ischemic stroke along with intracranial major artery changes in Japanese patients. These findings highlight the importance of considering ethnic and genetic differences in stroke prevention strategies.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"415 ","pages":"Article 120674"},"PeriodicalIF":5.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146187551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"tRF-GluCTC promotes VSMC apoptosis and oxidative stress by targeting TYRO3 in intracranial aneurysm","authors":"Chao Wang ,&nbsp;Bing Yu ,&nbsp;Zhenwen Cui ,&nbsp;Bing Chen ,&nbsp;Hongliang Zhang ,&nbsp;Shifang Li ,&nbsp;Pin Guo ,&nbsp;Tao Yu ,&nbsp;Yugong Feng","doi":"10.1016/j.atherosclerosis.2026.120700","DOIUrl":"10.1016/j.atherosclerosis.2026.120700","url":null,"abstract":"<div><h3>Background and aims</h3><div>tRNA-derived small RNAs (tsRNAs) have attracted growing attention for their involvement in various diseases, but their role in intracranial aneurysm (IA) remains unclear. This study aimed to investigate the potential of tsRNAs, specifically tRF-GluCTC, in the development and progression of IA.</div></div><div><h3>Methods</h3><div>High-throughput sequencing was performed to identify differentially expressed tsRNAs in the plasma exosomes of IA patients. The expression of tRF-GluCTC was analyzed in both exosomes and IA tissues. Functional assays in vascular smooth muscle cells (VSMCs) were conducted to examine the effects of tRF-GluCTC on apoptosis, oxidative stress, and inflammation. Bioinformatics analysis was used to predict and validate the target gene of tRF-GluCTC. In vivo experiments were carried out using an IA animal model to assess the impact of tRF-GluCTC knockdown on IA formation and vascular pathology.</div></div><div><h3>Results</h3><div>tRF-GluCTC was found to be significantly upregulated in both plasma exosomes and IA tissues. Functional assays revealed that tRF-GluCTC promotes apoptosis, oxidative stress, and inflammation in VSMCs. Mechanistically, tRF-GluCTC was shown to bind to the 3′UTR of its target gene TYRO3, leading to its downregulation and suppression of the PI3K/Akt signaling pathway, which modulates VSMC function. In animal models, knockdown of tRF-GluCTC attenuated IA formation, improved vascular pathology, and reduced VSMC apoptosis and oxidative stress. Additionally, both exosomal and free plasma tRF-GluCTC levels were elevated in IA patients, with exosomal tRF-GluCTC showing superior diagnostic performance compared to free plasma tRF-GluCTC.</div></div><div><h3>Conclusion</h3><div>These findings highlight the critical role of tRF-GluCTC in the pathogenesis of IA and its potential as a novel biomarker for diagnosis. Additionally, tRF-GluCTC may serve as a promising therapeutic target for the treatment of IA.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"415 ","pages":"Article 120700"},"PeriodicalIF":5.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147509072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cost-effectiveness of alternative cascade screening strategies for familial hypercholesterolemia with realistic cascade screening acceptance rates and use of novel treatment","authors":"Jing Lou ,&nbsp;Kok Joon Chong ,&nbsp;Sharon Li Ting Pek ,&nbsp;Yasmin Bylstra ,&nbsp;Chester Lee Drum ,&nbsp;Weng Khong Lim ,&nbsp;Yi Wang ,&nbsp;Khung Keong Yeo ,&nbsp;Subramaniam Tavintharan ,&nbsp;Hwee-Lin Wee","doi":"10.1016/j.atherosclerosis.2025.120416","DOIUrl":"10.1016/j.atherosclerosis.2025.120416","url":null,"abstract":"<div><h3>Background and aims</h3><div>Cascade screening (CS) for familial hypercholesterolemia (FH) has been found to be cost-effective in many published studies. However, most existing studies (i) ignored or overstated first-degree relative (FDR) participation rate (as 60–100 %), (ii) did not consider novel and expensive therapies, e.g. PCSK9 inhibitors (PCSK9i), and (iii) were conducted outside of Asia. This study, conducted in Singapore, where FDR participation rate is about 25 % among probands who have known pathogenic variants, aims to identify drivers of cost-effectiveness of CS protocols for FH.</div></div><div><h3>Methods</h3><div>Four CS protocols, which vary in the application of genetic tests, were examined using a hybrid decision tree-Markov model. Sensitivity analyses were conducted to identify drivers of cost-effectiveness.</div></div><div><h3>Results</h3><div>Cascade acceptance rates are key drivers of cost-effectiveness. Other drivers include age of proband, prevalence of FH among probands, health-related quality of life loss with cardiovascular disease, timeliness of starting treatment post-screening, treatment effectiveness, cost of PCSK9i and discount rate for cost and QALY. With cascade acceptance rates observed in Singapore, among various screening protocols examined, probabilities of being cost-effective ranged from 86 % to 95 % when no access to PCSK9i and ranged from 75 % to 98 % when PCSK9i are provided. The most cost-effective protocol differs depending on cascade acceptance rates and whether PCSK9i is provided.</div></div><div><h3>Conclusion</h3><div>For better cost-effectiveness of CS for FH, health systems need to look for ways to improve proband's willingness to share contact of their relatives and relatives' willingness to be screened and to lower the cost of novel treatment. Other ways to improve cost-effectiveness include to select age groups for proband screening, improve screening detection rate among probands, and start timely treatment post-screening.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"415 ","pages":"Article 120416"},"PeriodicalIF":5.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147740137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Silencing CCL5 suppresses ferroptosis to alleviate calcific aortic valve disease through chemokine pathway inhibition","authors":"Hongjin Zhang ,&nbsp;Wencheng Yan ,&nbsp;Jiayuan Ling ,&nbsp;Xing Shi ,&nbsp;Ping Lai ,&nbsp;Bei Wang ,&nbsp;Yongling Liao ,&nbsp;Hongzhou Zhang","doi":"10.1016/j.atherosclerosis.2026.120640","DOIUrl":"10.1016/j.atherosclerosis.2026.120640","url":null,"abstract":"<div><h3>Background</h3><div>Calcific aortic valve disease (CAVD) involves pathological mineralization, but the roles of chemokine signaling and ferroptosis remain unclear. This study investigated the regulatory function of C–C motif chemokine ligand 5 (CCL5) in CAVD progression via the chemokine pathway and ferroptosis.</div></div><div><h3>Methods</h3><div>Bioinformatics analysis and single-cell RNA sequencing analysis were performed to identify hub genes and potential cell types. Human aortic valve interstitial cells (VICs) were treated with osteogenic medium (OM) to induce calcification. Apoe^−/− mice were induced by a high-fat diet in vivo. Calcification, oxidative stress, and ferroptosis markers were assessed by pathological staining, enzyme-linked immunosorbent assay, and Western blot, respectively. Ferroptosis was modulated using Ferrostatin-1 (inhibitor) or Erastin (inducer), and chemokine signaling was activated with the CXC motif chemokine receptor 4 (CXCR4) agonist ATI-2341 TFA.</div></div><div><h3>Results</h3><div>CCL5 was identified as a key hub gene in CAVD. Knockdown of CCL5 significantly attenuated OM-induced VICs calcification, osteogenic differentiation, oxidative stress, and ferroptosis. Similar protective effects were observed in vivo, with reduced valve thickening and calcification in Apoe^−/− mice. Ferroptosis inhibition mirrored these effects, while its induction reversed CCL5-knockdown benefits. Furthermore, chemokine signaling pathway was screened as the downstream pathway of CCL5. Mechanistically, CCL5 knockdown suppressed CXCR4/CXCL12 expression. Activating chemokine signaling with TFA abolished the protective effects of CCL5 silencing on calcification, ferroptosis, and oxidative stress in vitro and in vivo.</div></div><div><h3>Conclusion</h3><div>CCL5 promoted CAVD progression by activating the chemokine signaling pathway to induce ferroptosis. Targeting CCL5 may offer a novel therapeutic strategy for CAVD.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"414 ","pages":"Article 120640"},"PeriodicalIF":5.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of LDL receptor-dependent lipid lowering therapies in patients with homozygous familial hypercholesterolemia according to functional genotype","authors":"G.B.John Mancini ,&nbsp;Arnold Ryomoto ,&nbsp;Isabelle Ruel ,&nbsp;Iulia Iatan ,&nbsp;Jacques Genest ,&nbsp;Frederick J. Raal ,&nbsp;Raul D. Santos ,&nbsp;Ana Paula Marte ,&nbsp;Brooke A. Kennedy ,&nbsp;Liam R. Brunham ,&nbsp;Daniel Gaudet ,&nbsp;Miriam Larouche ,&nbsp;Diane Brisson ,&nbsp;Robert A. Hegele ,&nbsp;the Canadian Homozygous Familial Hypercholesterolemia - HoFH Registry","doi":"10.1016/j.atherosclerosis.2026.120646","DOIUrl":"10.1016/j.atherosclerosis.2026.120646","url":null,"abstract":"<div><h3>Background and aims</h3><div>Patients with homozygous familial hypercholesterolemia (HoFH) respond to standard lipid lowering therapy (LLT) poorly due to biallelic abnormalities affecting low-density lipoprotein receptor (LDLR) function. Relatively little information stratified by functional genotyping is available.</div></div><div><h3>Methods</h3><div>We evaluated lowering of low-density lipoprotein cholesterol (LDL-C) with statins, statins plus ezetimibe or add-on proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors in 175 patients with HoFH according to <em>LDLR</em> functional genotyping (defective/defective = 119, defective/null = 38, null/null = 18).</div></div><div><h3>Results</h3><div>LLT resulted in significant LDL-C percent reductions in all 3 subgroups ranging from 17 ± 19 % (mean ± SD) in the null/null subgroup to 29 ± 21 % in the defective/defective subgroup. Achievement of ≥50 % LDL-C reduction was not seen in the null/null subgroup. Achievement of this plus LDL-C &lt; 2.6 mmol/L was seen only in the defective/defective subgroup but rarely (2.5 %, 3/119 patients). While responses to statin plus ezetimibe and add-on PCSK9 inhibitors were progressively and significantly attenuated in the defective/null and null/null subgroups, there was no difference according to functional genotyping in the response to statins. All 3 subgroups showed mean LDL-C lowering in the range of 25–29 % in response to statins.</div></div><div><h3>Conclusions</h3><div>LDLR-dependent LLT achieves significant LDL-C lowering in patients with HoFH which is modulated by functional genotyping except in the case of statins, possibly because of potential non-LDLR-dependent mechanisms of action. However, optimization of LDL-C remains rare and underscores the need for accessible and non-LDLR-dependent LDL-C lowering therapies.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"414 ","pages":"Article 120646"},"PeriodicalIF":5.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}